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dc.contributor.authorZhang, J
dc.date.accessioned2024-01-31T16:02:28Z
dc.date.issued2024-01-29
dc.date.updated2024-01-30T13:40:34Z
dc.description.abstractDiabetes mellitus (DM) is a global public health problem. Increasing evidence has shown that chronic low-grade inflammation contributes to the pathogenesis of diabetes and its associated complications. The primary symptom of diabetes, hyperglycaemia, and a common complication in insulin-treated diabetes, hypoglycaemia, both promote pro-inflammatory responses, although the mechanism remains not fully understood. It has also been revealed that metabolism is associated with inflammatory responses in immune cells. However whether targeting metabolism could serve as a potential therapeutic approach to alleviate diabetic inflammation remains unknown. This study focused on AMP-activated protein kinase (AMPK), a key regulator of metabolism, to explore its involvement in the regulation of inflammatory response in macrophages. In both peripheral macrophages and central macrophages, microglia, low glucose enhanced the release of a pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF), which has been observed to be elevated in people with diabetes and represents the severity of the disease. Importantly, the MIF release from macrophages was significantly suppressed by pharmacological AMPK activation. A similar trend was also noted in macrophages from mice with genetic activation using AMPKγ1 gain-of-function (D316A). These results suggest an anti-inflammatory role of AMPK during hypoglycaemia. Additionally, macrophages exposed to low glucose showed a transient activation of AMPK and metabolic adaptation with an increased ratio of oxidative phosphorylation to glycolysis to maintain ATP levels. However, this metabolic adaptation was significantly attenuated by potent pharmacological AMPK activation in short term though the ATP levels were not altered. Furthermore, pharmacological AMPK activation did not alter either autophagy or low glucose-induced oxidative stress in macrophages. Nevertheless, AMPK activation modestly reduced low glucose-induced nuclear translocation of NFĸB signalling and the inhibition of NFĸB signalling diminished low glucose-induced MIF release. This evidence suggests that the inhibitory effect of AMPK on low glucose-induced MIF release is mediated, at least in part, by limiting NFĸB signalling. Compared to peripheral macrophages, microglia displayed earlier elevation of MIF release and earlier cell death, suggesting increased vulnerability to low glucose-induced metabolic stress. Given that glucose is the major energy source in the brain, the protective role of pharmacological AMPK activation in microglia during hypoglycaemia is particularly important. Collectively, these findings confirmed the hypothesis, highlight the anti-inflammation role of AMPK in macrophages/microglia during low glucose exposure and suggest that pharmacological AMPK activation may be a novel strategy for combating inflammation in hypoglycaemia. 3 AMPK is a heterotrimeric complex, consisting of three subunits: α, β and γ subunits. Each subunit has two (α subunit and β subunit) or three (γ subunit) isoforms. Previous studies have suggested that different compositions of AMPK subunit isoforms may be involved in physiological or pathological processes, and AMPK isoforms exhibit distinct tissue-specific expression patterns that vary across species. Consequently, the pharmacological properties of AMPK activators may differ due to their isoform selectivity or bias. However, the distributions of AMPK isoforms in different tissues/species remain not fully elucidated. In this study, RNA-seq data analysis using open-source data (Gene Expression Omnibus) was performed to identify the composition of AMPK subunit isoforms expressed in various tissues across three species; mouse, rat and human. The in-sample abundance analysis revealed tissue and species differences in AMPK isoenzymes expressed. Furthermore, RNA-seq data analysis demonstrated that the abundance of AMPKα1 was increased along with a decrease in AMPKα2 expression in diabetic kidney, brain and skeletal muscle but not in other tested tissues. Additionally, stimulation with lipopolysaccharide (LPS) increased the percentage of AMPK γ1 expressed in macrophages/microglia. The mechanisms and physiological implications of these changes in the composition of AMPK subunit isoforms remain unclear. Nevertheless, these findings pave the way for future research elucidating the isoform-specific functions of AMPK and encouraging the development and application of AMPK activators/inhibitors with isoform selectivity.en_GB
dc.description.sponsorshipMedical Research Councilen_GB
dc.identifier.urihttp://hdl.handle.net/10871/135217
dc.language.isoenen_GB
dc.publisherUniversity of Exeteren_GB
dc.rights.embargoreasonThis thesis is embargoed until the 29/Jul/2025 as the author plans to publish their research.en_GB
dc.subjectMacrophagesen_GB
dc.subjectAMPKen_GB
dc.subjectDiabetesen_GB
dc.subjectinflammationen_GB
dc.subjectAMP-activated kinaseen_GB
dc.subjectMicrogliaen_GB
dc.subjectHypoglycaemiaen_GB
dc.subjectMacrophage migration inhibitory factoren_GB
dc.subjectPF-06409577en_GB
dc.subjectSBI-0206965en_GB
dc.subjectBI-9774en_GB
dc.titleTreating diabetic inflammation using AMP-activated protein kinase activatorsen_GB
dc.typeThesis or dissertationen_GB
dc.date.available2024-01-31T16:02:28Z
dc.contributor.advisorBeall, Craig
dc.contributor.advisorEllacott, Kate
dc.publisher.departmentCollege of Medicine and Health
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserveden_GB
dc.type.degreetitlePhD in Medical Studies
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctoral Thesis
rioxxterms.versionNAen_GB
rioxxterms.licenseref.startdate2024-12-12
rioxxterms.typeThesisen_GB


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